Normal oligodeoxynucleotides (ODNs) have been reported to have inhibitory effects on selected gene expression, primarily due to transcription arrest by mRNA duplex formation. However, these compounds are susceptible to digestion by cell nucleases. Nuclease-resistant ODN analogues containing methylphosphonate (P- Me) in place of phosphate has been developed to overcome this problem, but these compounds also have disadvantages, notably poor aqueous solubility and poor hybridizability. In order to overcome these difficulties, we have synthesized a series of phosphorothioate (P-S) analogs, which retain the charge of phosphate, but are nuclease-resistant. These compounds are being tested as agents against HIV and other lentiviruses, against herpes simplex Virus (a DNA virus), and several oncogenes (eg. myc) in lung cancer cells, and against genes related to drug resistance (eg. P-170 genes). Tests for toxicity in mice are also being conducted. A series of analogs with covalently attached groups on both the 3' and 5' ends of oligomers are being synthesized and will also be tested for biological activity in a cell free expression system, and in the systems tested above if further evidence of improved activity is discovered.